This project is focused on understanding the molecular mechanism by which laser trabeculoplasty (LTP) ameliorates elevated intraocular pressure (IOP) in open-angle glaucoma. Although LTP is a common treatment for glaucoma, its mechanism has not been understood. LTP has distinct limitations, but it is effective in many cases. Elucidation of the molecular details by which LTP reduces IOP will facilitate the design of novel alternative treatments or allow optimization of the current empirically- derived clinical LTP parameters. Recent studies demonstrate: 1) sustained increases in matrix metalloproteinase (MMP) expression within the juxtacanalicular trabecular meshwork (TM) in response to LTP and 2) that manipulation of trabecular MMP activity reversibly modulates aqueous outflow facility. Thus, LTP-induced extracellular matrix remodeling of the trabecular juxtacanalicular outflow resistance by these MMPs provides a plausible explanation for the efficacy of this therapy. This proposal is focused on developing a detailed molecular understanding of this process. Within eight hours after LTP treatment TM cells express a factor, which will trigger the LTP responses. Studies will include: 1) rigorous identification of the factor, apparently IL-1beta with augmentation by TNFalpha; 2) determining how LTP induces the factor(s); 3) evaluating the signal transduction and transcriptional activation pathways used by the factor to induce trabecular MMPs; and 4) investigating the effects of the factor on outflow facility in perfused human anterior segment organ culture. A combination of biochemical, molecular biological and physiological approaches will be used. Potential benefits of these studies include: 1) an improved molecular understanding of the mechanism of LTP action which will facilitate optimization of protocols for LTP; 2) new insights into the details of critical trabecular meshwork functions and responses; and 3) new information that can be used to develop novel alternative therapies for open-angle glaucoma based on increasing aqueous outflow facility.